A common culprit of skin and respiratory infections, Staphylococcus aureus is very unpredictable. Between 20 and 30 percent of people carry silent colonies on their skin and in their nostrils, which rarely cause problems beyond the occasional rash. But in some cases, these bacteria cause infections that lead to life-threatening complications, such as pneumonia, deep skin infections, and sepsis. Until recently, there was no way to predict which infections might turn deadly.
Now, a new study describes mutations that predispose patients to severe staph infections. The research, published in Science, identifies a mutated gene common to several patients who suffer from life-threatening staph infections and suggests that people living with a genetic condition known as 5p or Cri-du-chat syndrome may run a similar risk.
“We characterized severe Staphylococcus aureus infection at genetic, cellular, immunological and clinical levels,” says András Spaan, first author of the study. “By integrating these levels, we established causality and provided clues for future interventions.”
A first for the intrinsic immunity of cells
To better understand why S. aureus causes disease in some people but not others, scientists in the laboratory of Rockefeller immunologist Jean-Laurent Casanova examined the protein-coding genomes of more than 100 patients who had suffered from unexplained serious staphylococcal infections.
The common genetic thread linking some of these disparate patients was mutations in a gene called OTULIN, which is perched along the short arm of chromosome 5 and codes for an enzyme involved in regulating inflammation. These people weren’t entirely devoid of OTULIN – only one of their two copies of the gene was mutated – but this deficiency seemed to be all it took to leave them vulnerable to infections that would do little harm to anyone. other people.
Scientists expected to find that OTULIN deficiency somehow paralyzes white blood cells or prevents the immune system from smothering S. aureus. But further investigation revealed that these mutations indirectly cause an unrelated protein to clump together on the surface of skin and lung cells, erasing the tools these cells use to defend themselves against a toxin produced by S. aureus. This defense mechanism is known as intrinsic cellular immunity.
This discovery was particularly surprising because, until then, specific defects in cellular intrinsic immunity had only been linked to a predisposition to certain viral infections, from Covid to herpes to encephalitis. It had never been shown to play a role in bacterial diseases. “This is the first known case of intrinsic cellular immunodeficiency predisposing patients to bacterial infection,” says Spaan.
A bigger role for OTULIN
While the people studied by Spaan and colleagues lacked only one copy of OTULIN, people born without either functional copy of this gene face a host of early inflammatory diseases, which s are often fatal within the first year of life.
This observation led Spaan to conclude that a functional copy of OTULIN is sufficient to prevent inflammatory diseases, but insufficient to protect against life-threatening staph infections, a genetic mechanism known as haploinsufficiency. “The genetic mechanism was important to pin down,” says Spaan. “People with two working copies of the gene appear to be healthy, those without working copies have autoinflammatory disease, and those with one working copy are susceptible to serious staph infections.”
Given this general rule, the researchers hypothesized that any population missing a single copy of OTULIN would also be predisposed to serious infections. So they looked at a group of volunteers with 5p- syndrome, the most common chromosomal deletion disorder in humans characterized by developmental delays, intellectual disabilities and, in infants, high-pitched crying. Most patients with 5p syndrome lack the entire short arm of chromosome 5 and therefore invariably live their lives with only one functional copy of OTULIN.
Indeed, after examining six patients with 5p syndrome, the team found that a third were susceptible to lung infections. “We were able to demonstrate that this susceptibility is driven by the fact that they only had one functional copy of OTULIN,” says Spaan. “In many ways, these patients genetically resembled the patients we had identified with severe staph infections.”
“Both clinically and on a cellular level, you could almost say they have the same disease.”
The results do not imply that everyone with OTULIN haploinsufficiency or 5p syndrome will develop serious infections. In fact, early study results suggest that only 30% of people with these mutations develop serious disease. Why OTULIN haploinsufficiency appears to cause disease in some patients but not others – a common phenomenon that genetic researchers call “incomplete penetrance” – will be the subject of follow-up studies.
“Many genetic diseases act this way, but it’s still confusing,” says Spaan. “Why are some people with these mutations completely healthy, while others get very sick and may even die? »
A potential answer has already surfaced. Spaan and colleagues found that people with OTULIN mutations but no signs of severe disease had elevated levels of antibodies that neutralize the toxin produced by S. aureus, possibly due to previous exposure to common skin bacteria. . People with severe disease, on the other hand, had very few antibodies.
Further research into the genetic predisposition to diseases, especially those as difficult to treat as staphylococcal infections, could help in the development of future therapeutics. “Studies of these disorders can serve as a compass,” says Spaan, “Our research clarifies host-pathogen interactions, revealing scientific insights into pathogenesis and immunity.”
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